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Repurposing Styrene Catabolic Enzymes for the Synthesis of Penicillins

Award Number: R16GM145453
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Repurposing Styrene Catabolic Enzymes for the Synthesis of Penicillins - Abstract Penicillins represent one of the most impactful antibiotics in use for the resolution of gram-positive bacterial infections including bacterial meningitis, diptheria, strep throat, syphilis, gonorrhea, and yaws disease that afflict more than 6 million people annually. These antibiotics are frequently in short supply and improved production methods are needed that both increase the accessibility while reducing inefficiency and environmental impacts associated with current production methods. The primary route to the commercial production of penicillins begins with batch fermentation of the fungus, P. chrysogenum as a biosynthetic route to 6-aminopenicillanic acid (6-APA), which is subsequently used as a starting material for the synthesis of b-lactam antibiotics. As an alternative to currently employed organic synthetic routes to amidation of 6-APA, chemoenzymatic synthetic methods based on the amidation of 6-APA by penicillin amidases (PAs) or isopenicillanic acid transferases (IATs) provide a competitive green chemical approach to penicillin-based antibiotics. Each chemoenzymatic approach poses unique challenges. The amidase-catalyzed acylation of 6-APA requires the use of chemically activated carboxylic acid derivatives as substrates and proceeds with low transformation efficiency. IATs on the other hand are dependent on phenylacetyl- Coenzyme A ligases, which have low stability and limited substrate specificity. In the present work we target an alternate chemoenzymatic strategy for the synthesis of penicillins from aldehydes by joining the activities of IAT and an engineered thiol-acylating aldehyde dehydrogenase (TAD). The first specific aim of this work will target the selective introduction of mutations in the catalytic active site of phenylacetaldehyde dehydrogenase (NPADH) from Pseudomonas putidia (S12), which has a broad aldehyde specificity. Mutations will target the transformation of NPADH into a TAD for the synthesis of the N-acetylcysteamine (SNAc) thioesters. In our second aim, SNAc thiosesters, which are surrogates of acyl-CoA will be introduced with 6- APA co-substrates in the IAT-catalyzed synthesis of penicillins. This strategy is expected to result in a high product yield while eliminating the limitations associated with the phenylacetyl CoA ligases. The development this process will serve as prototypical green-chemistry pathway that can be further expanded into a platform for the production of existing and new classes of b-lactam antibiotics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $155,000 )
2024	2024	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	3	9/13/2024	NON-COMPETING CONTINUATION	$155,000
														Subtotal = $155,000

Issue Date FY: 2023 ( Subtotal = $155,000 )
2023	2023	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE BUILDING NAD ROOM 358C	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	2	8/3/2023	NON-COMPETING CONTINUATION	$155,000
														Subtotal = $155,000

Issue Date FY: 2022 ( Subtotal = $155,000 )
2022	2022	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE BUILDING NAD ROOM 358C	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	1	8/19/2022	NEW	$155,000
														Subtotal = $155,000

Grand Total All Awards = $465,000

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Repurposing Styrene Catabolic Enzymes for the Synthesis of Penicillins

Award Number: R16GM145453

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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